Narcolepsy-cataplexy affects 0.05% of the US population. The cause of the disorder is a loss of hypocretin/orexin neurons in the hypothalamus, of likely autoimmune origin. The disease is uniquely tightly associated with Human Leukocyte Antigen (HLA) DQB1*0602, and may serve as a model to the study of other autoimmune diseases affecting the brain. A weaker association with the T-Cell receptor (TCR) loci is also found. The focus of this application is to sequence the HLA-DQA1 and DQB1 exons and promoter region in 4,000 controls and 3,500 patients with DQB1*0602 like haplotypes. Patients and controls will include Asians, Caucasians and African Americans. The ultimate goal of this project is to determine which DQA1 and DQB1 amino acids are involved in disease susceptibility, and to model the DQ heterodimer binding site involved. Together with work ongoing in the TCR arena, this project offers the opportunity to model the HLA-peptide-TCR trimolecular complex involved in narcolepsy susceptibility. It will also make use of the newly developed FLX 454 titanium sequencing technique to generate and analyze high throughput, low cost full HLA DQA1 and DQB1 sequence, and to develop and perfect new statistical analytic tools, such as the Sequence Variant Type Analysis (SFVT), for disease association studies. PUBLIC HEALTH RELEVANCE (provided by applicant): Narcolepsy affects 1/2000 Americans and is a common neurological disorder. The proposed study may lead to new therapeutic avenues for the disorder.